The invention relates to a spiro [cyclohexane-1, 3apos; -indoline]-2, 5-diene-2apos,-2, 5-diene-2apos; photocatalytic synthesis method and application of-ketone

Abstract

The invention discloses a method for synthesizing spiro [cyclohexane-1, 3 '-indoline]-2, 5-diene-2'-ketone compounds, which comprises the following specific steps: sequentially adding N-biphenyl oxalic acid compounds, alkali and a catalyst into a reaction container, vacuumizing and backfilling for multiple times by using argon, adding a solvent, and reacting under the conditions of argon atmosphere and visible light irradiation, thereby obtaining the spiro [cyclohexane-1, 3 '-indoline]-2, 5-diene-2'-ketone compounds. And stirring and reacting at room temperature to obtain the target product spiro [cyclohexane-1, 3 '-indoline]-2, 5-diene-2'-ketone compound. The preparation method disclosed by the invention is simple, convenient and safe to operate, mild in reaction condition and good in functional group tolerance, a light source of the method is visible light and is green and pollution-free, and the catalyst and a reaction medium are relatively friendly to the environment. Part of target compounds synthesized by the invention show remarkable antitumor activity and can be further used for preparing antitumor drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis and anti-tumor application of spirocyclic compounds, and specifically relates to a photocatalytic synthesis method and application of spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compounds. Background Art

[0002] Spiroindoline nuclei have unique quaternary carbon stereocenters that can give compounds excellent pharmacological properties, such as improved affinity with target proteins, solubility, and pharmacokinetic properties, and are therefore widely used in marketed drugs and candidate drugs (Eur. J. Med. Chem. 2015, 97, 673-698; Eur. J. Med. Chem. 2021, 216, 113334). Therefore, the development of methods for constructing spiroindolines has important theoretical significance and application value for synthetic chemistry and the pharmaceutical industry.

[0003] Spirohexadienindoline is a novel spiroindolinone compound. At present, the most commonly used strategy for constructing this structure is that aryl iodide (or bromine compound) generates aryl radicals by dehalogenation, followed by intramolecular free radical cycloaddition reaction. For example, in 2004, Tanaka et al. reported a method for constructing the parent nucleus using N-(2-iodophenyl)benzamide as a raw material under the action of excessive SmI2 (Chem. Commun. 2004, 2228-2229). These methods have the problems of using toxic SmI2 as an additive and being unable to realize the synthesis of halogenated (bromine or iodine) derivatives. Therefore, it is of great significance to develop a new method for synthesizing spirohexadienindoline compounds using brand-new raw materials, halogen substituent tolerance, and no toxic reagents. Summary of the invention

[0004] The technical problem solved by the present invention is to provide a photocatalytic synthesis method of spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compounds which is driven by visible light, does not involve transition metals and does not use toxic reagents, so as to effectively solve the technical problems such as incompatibility of halogen substituents and the need for toxic reagents in the synthesis of spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compounds. The spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compounds synthesized by the method have good anti-tumor activity and can be used for further preparation of anti-tumor drugs.

[0005] The present invention adopts the following technical scheme to solve the above technical problems. A method for synthesizing a spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compound is characterized by the specific steps of: sequentially adding an N-biphenyl oxalic acid compound, a base and a catalyst into a reaction container, then vacuuming and backfilling with argon gas for multiple times, adding a solvent, and stirring and reacting at room temperature under argon atmosphere and visible light irradiation to obtain a target product, a spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compound, wherein the structural formula of the N-biphenyl oxalic acid compound is shown in Formula A, and the structural formula of the spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compound is shown in Formula B:

[0006]

[0007] Wherein R1 is an alkyl group or a substituted alkyl group, and the substituent of the substituted alkyl group is an alkenyl group, an alkynyl group, a phenyl group, an alkoxy group, a trifluoromethyl group, a halogen group or a drug molecule group; R2 is an alkyl group, an alkoxy group, a trifluoromethyl group or a halogen group; R3 is an alkyl group, an alkoxy group, a trifluoromethyl group or a halogen group; the base is one or more of lithium hydroxide, cesium carbonate, potassium hydroxide, potassium carbonate or sodium carbonate; the catalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4-CzIPN), and the structural formula of the catalyst is:

[0008]

[0009] It is further defined that the alkyl group in R1 is C 1-10 Alkyl, the substituted alkyl in R1 is C 1-10 Substituted alkyl; the alkyl in R2 is C 1-10 Alkyl, the alkoxy group in R2 is C 1-10 Alkoxy; the alkyl group in R3 is C 1-10 Alkyl, the alkoxy group in R3 is C 1-10 Alkoxy.

[0010] It is further defined that the solvent is a mixed solvent of N-methylpyrrolidone and water (NMP / H2O), wherein the volume ratio of N-methylpyrrolidone to water is 80:1.

[0011] It is further defined that the structural formula of the spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compound is specifically:

[0012]

[0013] It is further defined that the molar ratio of the N-biphenyl oxalic acid compound, the base and the catalyst is: 1:1-3:0.01-0.1.

[0014] It is further defined that the specific synthetic route in the synthetic method of the spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compound is:

[0015]

[0016] It is further defined that the visible light irradiation condition is to use a blue LED lamp as the visible light source, with a wavelength of 455nm and a power of 10W.

[0017] The invention discloses an application of the spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compounds in the preparation of anti-tumor drugs.

[0018] Compared with the prior art, the present invention has the following advantages and beneficial effects: The present invention provides a method for preparing spiro[cyclohexane-1,3′-indoline]-2,5-diene-2′-one compounds using N-2-biphenyl oxalic acid as a raw material. Compared with the prior art, the preparation method of the present invention tolerates substituents such as bromine or iodine, and does not require the use of toxic reagents. The preparation method of the present invention is simple and safe to operate, has mild reaction conditions, and has good tolerance to functional groups. The light source of the method is visible light, which is green and pollution-free, and the catalyst and reaction medium are also relatively friendly to the environment. Some of the target compounds synthesized by the present invention show significant anti-tumor activity and can be further used to prepare anti-tumor drugs. DETAILED DESCRIPTION

[0019] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0020] Example 1

[0021] 2-([1,1′-biphenyl]-2-yl(methyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron. After vacuuming and backfilling with Ar gas three times, NMP / H2O (volume ratio 80:1, 3mL) was added. Under an argon atmosphere, a blue LED light with a power of 10W and a wavelength of 455nm was irradiated for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a white solid. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 73%. The structural formula of the target product is as follows:

[0022]

[0023] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0024] 1 H NMR (400MHz, CDCl3) δ7.31-7.26(m,1H),7.12(dd,J=7.2,0.8Hz,1H),7.08-7.04(m,1H),6. 84(d,J=8.0Hz,1H),6.15-6.11(m,2H),5.41-5.37(m,2H),3.23(s,3H),3.02-2.81(m,2H).

[0025] 13 C NMR (100MHz, CDCl3) δ178.0,143.1,134.3,128.5,127.4,124.9,124.0,123.1,108.1,51.9,26.7,25.9.

[0026] HRMS Calcd for C 14 H 14 NO[M+H] + :m / z 212.1070,Found:212.1068.

[0027] Example 2

[0028] 2-([1,1′-biphenyl]-2-yl(hexyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, irradiate with a blue LED light with a power of 10W and a wavelength of 455nm for 24h, and stir the reaction at room temperature. After the reaction is completed, quench the reaction with saturated NaCl aqueous solution (5mL) and extract with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(hexyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 56%. The structural formula of the target product is as follows:

[0029]

[0030] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0031] 1 H NMR (400MHz, CDCl3) δ7.29-7.24(m,1H),7.12(dd,J=7.2,0.8Hz,1H),7.06-7.02(m,1H),6.85(d,J=7.6Hz,1H),6.15-6.11(m, 2H), 5.40-5.36 (m, 2H), 3.70 (t, J = 7.2Hz, 2H), 3.02-2.81 (m, 2H), 1.72-1.65 (m, 2H), 1.37-1.29 (m, 6H), 0.87 (t, J = 7.2Hz, 3H).

[0032] 13 C NMR (100MHz, CDCl3) δ177.8,142.6,134.6,128.5,127.4,125.0,124.1,122.8,108.4,51.9,40.4,31.6,27.5,26.6,25.9,22.6,14.1.

[0033] HRMS Calcd for C 19 H 24 NO[M+H] + :m / z 282.1852,Found:282.1850.

[0034] Example 3

[0035] 2-([1,1′-biphenyl]-2-yl(octyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on 2-([1,1′-biphenyl]-2-yl(octyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 55%. The structural formula of the target product is as follows:

[0036]

[0037] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0038] 1 H NMR (600MHz, CDCl3) δ7.28-7.25(m,1H),7.12(d,J=6.6Hz,1H),7.05-7.03(m,1H),6.85(d,J=7.8Hz,1H),6.14-6.12(m,2H) ,5.39-5.37(m,2H),3.70(t,J=7.2Hz,2H),3.00-2.83(m,2H),1.71-1.66(m,2H),1.36-1.23(m,10H),0.87(t,J=7.2Hz,3H).

[0039] 13 C NMR (150MHz, CDCl3) δ177.8,142.6,134.6,128.5,127.4,125.0,124.1,122.8,108.4,51.9,40.4,31.9,29.4,29.3,27.5,27.0,25.9,22.8,14.2.

[0040] HRMS Calcd for C 21 H 28 NO[M+H] + :m / z 310.2165,Found:310.2163.

[0041] Example 4

[0042] 2-([1,1′-biphenyl]-2-yl(isopentyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(isopentyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 56%. The structural formula of the target product is as follows:

[0043]

[0044] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0045] 1 H NMR (600MHz, CDCl3) δ7.28-7.25(m,1H),7.12(d,J=7.2Hz,1H),7.05-7.03(m,1H),6.84(d,J=7.8Hz,1H),6.14-6.12(m,2H) ,5.39-5.37(m,2H),3.72(t,J=7.2Hz,2H),3.00-2.82(m,2H),1.68-1.63(m,1H),1.59-1.55(m,2H),0.98(d,J=6.6Hz,6H).

[0046] 13 C NMR (150MHz, CDCl3) δ177.8,142.5,134.6,128.5,127.4,125.1,124.1,122.8,108.4,51.9,38.8,36.2,26.1,25.9,22.6.

[0047] HRMS Calcd for C 18 H 22 NO[M+H] + :m / z 268.1696,Found:268.1692.

[0048] Example 5

[0049] 2-([1,1′-biphenyl]-2-yl(isopropyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(isopropyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 46%. The structural formula of the target product is as follows:

[0050]

[0051] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0052] 1 H NMR (400MHz, CDCl3) δ7.27-7.22(m,1H),7.12(dd,J=7.2Hz,1.2Hz,1H),7.05-7.00(m,2H),6.1 5-6.11(m,2H),5.40-5.36(m,2H),4.66-4.59(m,1H),3.01-2.80(m,2H),1.49(d,J=6.8Hz,6H).

[0053] 13 C NMR (100MHz, CDCl3) δ177.6,141.7,134.9,128.2,127.3,125.2,124.2,122.5,109.9,51.8,44.1,25.9,19.5.

[0054] HRMS Calcd for C 16 H 18 NO[M+H] + :m / z 240.1383,Found:240.1385.

[0055] Example 6

[0056] 2-([1,1′-biphenyl]-2-yl(2-ethylhexyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, irradiate with a blue LED light with a power of 10W and a wavelength of 455nm for 24h, and stir the reaction at room temperature. After the reaction is completed, quench the reaction with saturated NaCl aqueous solution (5mL) and extract with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(2-ethylhexyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 58%. The structural formula of the target product is as follows:

[0057]

[0058] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0059] 1 H NMR (400MHz, CDCl3) δ7.28-7.24(m,1H),7.12(d,J=6.4Hz,1H),7.06-7.02(m,1H),6.83(d,J=7.6Hz,1H),6.15-6.11(m, 2H),5.39-5.37(m,2H),3.65-3.55(m,2H),3.02-2.81(m,2H),1.89-1.82(m,1H),1.39-1.28(m,8H),0.94-0.86(m,6H).

[0060] 13 C NMR (100MHz, CDCl3) δ178.2,142.9,134.5,128.4,127.4,125.0,124.19,124. 16,122.7,108.7,51.9,44.4,37.4,30.8,28.8,25.9,24.1,23.2,14.2,10.8.

[0061] HRMS Calcd for C 21 H 28 NO[M+H] + :m / z 310.2165,Found:310.2162.

[0062] Example 7

[0063] 2-([1,1′-biphenyl]-2-yl(cyclopropylmethyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, irradiate with a blue LED light with a power of 10W and a wavelength of 455nm for 24h, and stir the reaction at room temperature. After the reaction is completed, quench the reaction with saturated NaCl aqueous solution (5mL) and extract with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(cyclopropylmethyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 52%. The structural formula of the target product is as follows:

[0064]

[0065] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0066] 1 H NMR (400MHz, CDCl3) δ7.30-7.26(m,1H),7.13(dd,J=7.2,1.2Hz,1H),7.07-7.03(m,1H),6.93(d,J=8.0Hz,1H),6.16-6.12(m ,2H),5.43-5.39(m,2H),3.61(d,J=6.8Hz,2H),3.02-2.81(m,2H),1.23-1.16(m,1H),0.54-0.50(m,2H),0.42-0.38(m,2H).

[0067] 13 C NMR (100MHz, CDCl3) δ178.0,142.8,134.5,128.4,127.3,125.0,124.1,122.8,108.6,52.0,44.6,25.9,9.8,3.9.

[0068] HRMS Calcd for C 17 H 18 NO[M+H] + :m / z 252.1383,Found:252.1382.

[0069] Example 8

[0070] 2-([1,1′-biphenyl]-2-yl(but-3-en-1-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(but-3-en-1-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 57%. The structural formula of the target product is as follows:

[0071]

[0072] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0073] 1 H NMR (400MHz, CDCl3) δ7.29-7.25(m,1H),7.12(dd,J=7.2,0.8Hz,1H),7.07-7.03(m,1H),6.85(d,J=8.0Hz,1H),6.15-6.11(m ,2H),5.86-5.76(m,1H),5.38-5.35(m,2H),5.06-5.01(m,2H),3.79(t,J=7.2Hz,2H),3.01-2.81(m,2H),2.48-2.43(m,2H).

[0074] 13 C NMR (100MHz, CDCl3) δ177.9,142.3,134.6,134.5,128.4,127.4,125.1,124.1,122.9,117.7,108.4,51.9,39.5,31.9,25.9.

[0075] HRMS Calcd for C 17 H 18 NO[M+H] + :m / z 252.1383,Found:252.1383.

[0076] Example 9

[0077] 2-([1,1′-biphenyl]-2-yl(prop-2-yn-1-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. The reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(prop-2-yn-1-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 60%. The structural formula of the target product is as follows:

[0078]

[0079] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0080] 1 H NMR (400MHz, CDCl3) δ7.33-7.29(m,1H),7.15-7.06(m,3H),6.17-6.13(m,2H),5. 43-5.39(m,2H),4.52(d,J=2.4Hz,2H),3.02-2.82(m,2H),2.24(t,J=2.4Hz,1H).

[0081] 13 C NMR (100MHz, CDCl3) δ177.0,141.1,134.2,128.5,127.6,125.0,123.6,123.5,109.3,77.1,72.6,51.8,29.8,25.9.

[0082] HRMS Calcd for C 16 H 14 NO[M+H] + :m / z 236.1070,Found:236.1076.

[0083] Example 10

[0084] 2-([1,1′-biphenyl]-2-yl(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(2-(tert-butoxy)-2-oxyethyl)amino)-2-oxyacetic acid as 100%, the yield of the target product is 55%. The structural formula of the target product is as follows:

[0085]

[0086] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0087] 1 H NMR (400MHz, CDCl3) δ7.27-7.23(m,1H),7.13(dd,J=7.2,1.2Hz,1H),7.08-7.04(m,1H),6.70(d, J=7.6Hz,1H),6.16-6.12(m,2H),5.45-5.42(m,2H),4.37(s,2H),3.02-2.82(m,2H),1.43(s,9H).

[0088] 13 C NMR (100MHz, CDCl3) δ177.9,166.6,141.9,134.0,128.5,127.4,125.1,123.9,123.3,108.2,82.7,51.8,42.5,28.1,25.9.

[0089] HRMS Calcd for C 19 H 22 NO3[M+H] + :m / z 312.1594,Found:312.1592.

[0090] Embodiment 11

[0091] 2-([1,1′-biphenyl]-2-yl(3-((tert-butyloxycarbonyl)amino)propyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(3-((tert-butyloxycarbonyl)amino)propyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 56%. The structural formula of the target product is as follows:

[0092]

[0093] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0094] 1H NMR (600MHz, CDCl3) δ7.28-7.26(m,1H),7.13(d,J=7.2Hz,1H),7.07-7.05(m,1H),6.86(d,J=7.8Hz,1H),6.16-6.13(m,2H),5. 44(s,1H),5.37(d,J=10.2Hz,2H),3.80(t,J=6.0Hz,2H),3.11-3.08(m,2H),3.00-2.84(m,2H),1.86-1.82(m,2H),1.41(s,9H).

[0095] 13C NMR (150MHz, CDCl3) δ178.9,156.2,141.9,134.5,128.6,127.6,125.2,123.8,123.3,108.4,79.1,52.0,37.4,36.9,28.5,27.3,25.8.

[0096] HRMS Calcd for C21H27N2O3[M+H]+:m / z 355.2016,Found:355.2016.

[0097] Example 12

[0098] 2-([1,1′-biphenyl]-2-yl(benzyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(benzyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 54%. The structural formula of the target product is as follows:

[0099]

[0100] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0101] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,5H),7.18-7.12(m,2H),7.04-7.00(m,1H),6.72(d ,J=7.6Hz,1H),6.19-6.15(m,2H),5.47-5.44(m,2H),4.92(s,2H),3.05-2.84(m,2H).

[0102] 13 C NMR (100MHz, CDCl3) δ178.1,142.2,136.0,134.4,128.9,128.5,127.8,127.6,127.5,125.0,124.0,123.1,109.2,52.0,44.2,25.9.

[0103] HRMS Calcd for C 20 H 18 NO[M+H] + :m / z 288.1383,Found:288.1380.

[0104] Embodiment 13

[0105] 2-([1,1′-biphenyl]-2-yl(phenylethyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-([1,1′-biphenyl]-2-yl(phenethyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 49%. The structural formula of the target product is as follows:

[0106]

[0107] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0108] 1 H NMR (600MHz, CDCl3) δ7.29-7.27(m,2H),7.25-7.20(m,4H),7.10(dd,J=7.2,0.6Hz,1H),7.05-7.02(m,1H),6.80(d, J=7.8Hz,1H),6.13-6.10(m,2H),5.32-5.30(m,2H),3.95(t,J=7.2Hz,2H),3.00(t,J=7.2Hz,2H),2.98-2.81(m,2H).

[0109] 13 C NMR (100MHz, CDCl3) δ177.7,142.3,138.2,134.4,129.0,128.7,128.4,127.3,126.8,125.1,124.0,122.9,108.3,51.8,41.7,33.7,25.9.

[0110] HRMS Calcd for C 21 H 20 NO[M+H] + :m / z 302.1539,Found:302.1537.

[0111] Embodiment 14

[0112] 2-(Methyl(5-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED lamp with a power of 10W and a wavelength of 455nm was irradiated for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-(methyl(5-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 54%. The structural formula of the target product is as follows:

[0113]

[0114] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0115] 1 H NMR(600MHz, CDCl3)δ7.08(d,J=7.8Hz,1H),6.94(s,1H),6.73(d,J=7.8Hz,1H),6 .14-6.11(m,2H),5.40-5.37(m,2H),3.21(s,3H),3.00-2.83(m,2H),2.32(s,3H).

[0116] 13 C NMR (150MHz, CDCl3) δ178.0,140.8,134.4,132.7,128.8,127.3,125.7,124.2,107.9,52.0,26.8,25.9,21.2.

[0117] HRMS Calcd for C 15 H 16 NO[M+H] + :m / z 226.1226,Found:226.1223.

[0118] Embodiment 15

[0119] 2-(Methyl(4-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-(methyl(4-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 59%. The structural formula of the target product is as follows:

[0120]

[0121] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0122] 1 H NMR(600MHz, CDCl3)δ7.00(d,J=7.8Hz,1H),6.87(d,J=7.2Hz,1H),6.67(s,1H),6 .13-6.10(m,2H),5.38-5.36(m,2H),3.21(s,3H),2.99-2.81(m,2H),2.39(s,3H).

[0123] 13 C NMR (150MHz, CDCl3) δ178.4,143.2,138.8,131.5,127.2,124.6,124.2,123.5,109.1,51.7,26.7,25.9,22.0.

[0124] HRMS Calcd for C 15 H 16 NO[M+H] + :m / z 226.1226,Found:226.1227.

[0125] Example 16

[0126] 2-((5-methoxy-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, irradiate with a blue LED lamp with a power of 10W and a wavelength of 455nm for 24h, and stir the reaction at room temperature. The reaction was quenched with saturated aqueous NaCl solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-((5-methoxy-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 48%. The structural formula of the target product is as follows:

[0127]

[0128] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0129] 1 H NMR (400MHz, CDCl3) δ6.81 (dd, J=8.4, 2.4Hz, 1H), 6.75-6.73 (m, 2H), 6.15-6 .11(m,2H),5.41-5.37(m,2H),3.78(s,3H),3.20(s,3H),3.03-2.81(m,2H).

[0130] 13 C NMR (100MHz, CDCl3) δ177.7,156.6,136.7,135.7,127.5,124.0,113.2,112.0,108.5,56.0,52.4,26.9,25.9.

[0131] HRMS Calcd for C 15 H 16 NO2[M+H] + :m / z 242.1176,Found:242.1175.

[0132] Embodiment 17

[0133] 2-(Methyl(5-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-(methyl(5-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 57%. The structural formula of the target product is as follows:

[0134]

[0135] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0136] 1 H NMR (400MHz, CDCl3) δ7.57(dd,J=8.0,0.8Hz,1H),7.34(d,J=1.2Hz,1H),6.91(d,J =8.0Hz,1H),6.20-6.16(m,2H),5.38-5.34(m,2H),3.26(s,3H),3.04-2.84(m,2H).

[0137] 13 C NMR (150MHz, CDCl3) δ177.9,146.1,134.9,128.2,126.3(q,J=4.5Hz),125.4(q,J=3 3.0Hz), 124.5 (q, J = 270.0Hz), 123.0, 122.1 (q, J = 3.0Hz), 107.9, 51.7, 27.0, 25.8. 19 F NMR (565 MHz, CDCl3) δ -61.4.

[0138] HRMS Calcd for C 15 H 13 F3NO[M+H] + :m / z 280.0944,Found:280.0940.

[0139] Embodiment 18

[0140] 2-((5-chloro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED lamp with a power of 10W and a wavelength of 455nm was irradiated for 24h, and the reaction was stirred at room temperature. The reaction was quenched with a saturated aqueous NaCl solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-((5-chloro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 51%. The structural formula of the target product is as follows:

[0141]

[0142] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0143] 1 H NMR (600MHz, CDCl3) δ7.26-7.25(m,1H),7.09(d,J=2.4Hz,1H),6.76(d,J=7.8 Hz,1H),6.17-6.14(m,2H),5.37-5.36(m,2H),3.21(s,3H),3.00-2.84(m,2H).

[0144] 13 C NMR (150MHz, CDCl3) δ177.6,141.7,135.9,128.49,128.46,127.9,125.5,123.3,109.1,52.0,26.9,25.9.

[0145] HRMS Calcd for C 14 H 13 ClNO[M+H] + :m / z 246.0680,Found:246.0678.

[0146] Embodiment 19

[0147] 2-((5-bromo-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a white oil. Based on the molar amount of 2-((5-bromo-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 42%. The structural formula of the target product is as follows:

[0148]

[0149] The white oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0150] 1 H NMR (400MHz, CDCl3) δ7.42-7.39(m,1H),7.22(d,J=2.0Hz,1H),6.71(d,J=8.4 Hz,1H),6.17-6.13(m,2H),5.38-5.34(m,2H),3.21(s,3H),3.00-2.83(m,2H).

[0151] 13 C NMR (150MHz, CDCl3) δ177.5,142.2,136.2,131.4,128.2,128.0,123.3,115.7,109.6,51.9,26.9,25.8.

[0152] HRMS Calcd for C 14 H 13 BrNO[M+H] + :m / z 290.0175,Found:290.0171.

[0153] Embodiment 20

[0154] 2-((5-iodo-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, irradiation was performed with a blue LED lamp with a power of 10W and a wavelength of 455nm for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a brown oil. Based on the molar amount of 2-((5-iodo-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 36%. The structural formula of the target product is as follows:

[0155]

[0156] The brown oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0157] 1 H NMR(400MHz, CDCl3) δ7.60(dd,J=8.0,1.6Hz,1H),7.38(d,J=2.0Hz,1H),6.62(d,J =8.0Hz,1H),6.17-6.13(m,2H),5.37-5.34(m,2H),3.20(s,3H),3.01-2.81(m,2H).

[0158] 13 C NMR (150MHz, CDCl3) δ177.3,142.9,137.4,136.6,133.8,128.0,123.3,110.2,85.6,51.8,26.8,25.9.

[0159] HRMS Calcd for C 14 H 13 INO[M+H] + :m / z 338.0036,Found:338.0033.

[0160] Embodiment 21

[0161] 2-(Methyl(3′-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-(methyl(3′-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 52%. The structural formula of the target product is as follows:

[0162]

[0163] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0164] 1 H NMR (600MHz, CDCl3) δ7.29-7.26(m,1H),7.09-7.03(m,2H),6.83(d,J=7.8Hz,1H),6.14-6 .12(m,1H),5.39-5.37(m,1H),5.10(s,1H),3.22(s,3H),2.90-2.73(m,2H),1.80(s,3H).

[0165] 13 C NMR (150MHz, CDCl3) δ178.4,143.2,135.1,134.6,128.4,127.6,124.8,123.8,123.0,118.6,108.1,53.2,30.8,26.7,23.5.

[0166] HRMS Calcd for C 15 H 16 NO[M+H] + :m / z 226.1226,Found:226.1225.

[0167] Embodiment 22

[0168] 2-(Methyl(2′-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid (0.2mmol), LiOH (2.5 equivalents, 0.5mmol) and catalyst 4CzIPN (5mol%) were added to a 10mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3mL) was added after vacuuming and backfilling with Ar gas three times. Under argon atmosphere, 10W blue LED light with a wavelength of 455nm was used for 24h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated NaCl aqueous solution (5mL) and extracted with ethyl acetate (3×15mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-(methyl(2′-methyl-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 56%. The structural formula of the target product is as follows:

[0169]

[0170] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0171] 1 H NMR (400MHz, CDCl3) δ7.30-7.27(m,1H),7.09-7.04(m,2H),6.84(d,J=8.0Hz,1H),6.09-6.05(m, 1H),5.85-5.84(m,1H),5.34-5.30(m,1H),3.25(s,3H),3.01-2.83(m,2H),1.32(d,J=1.6Hz,3H).

[0172] 13 C NMR (100MHz, CDCl3) δ178.1,143.7,133.7,129.8,128.4,126.7,124.5,124.4,123.7,123.1,108.0,55.4,27.1,26.7,19.0.

[0173] HRMS Calcd for C 15 H 16 NO[M+H] + :m / z 226.1226,Found:226.1225.

[0174] Embodiment 23

[0175] 2-((3′-methoxy-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2 mmol), LiOH (2.5 equivalents, 0.5 mmol) and catalyst 4CzIPN (5 mol%) were added to a 10 mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3 mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED light with a power of 10 W and a wavelength of 455 nm was irradiated for 24 h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-((3′-methoxy-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 53%. The structural formula of the target product is as follows:

[0176]

[0177] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0178] 1 H NMR (400MHz, CDCl3) δ7.30-7.26(m,1H),7.11(dd,J=7.2,1.2Hz,1H),7.07-7.03(m,1H),6.84(d,J=7.6H z,1H),6.05-6.01(m,1H),5.34-5.30(m,1H),4.37(s,1H),3.53(s,3H),3.23(s,3H),3.06-2.86(m,2H).

[0179] 13 C NMR (100MHz, CDCl3) δ178.8,156.4,142.9,134.9,128.4,126.3,124.8,124.3,123.0,108.1,92.5,54.2,53.4,28.6,26.7.

[0180] HRMS Calcd for C 15 H 16 NO2[M+H] + :m / z 242.1176,Found:242.1175.

[0181] Embodiment 24

[0182] 2-((2′-fluoro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2 mmol), LiOH (2.5 equivalents, 0.5 mmol) and catalyst 4CzIPN (5 mol%) were added to a 10 mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3 mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED light with a power of 10 W and a wavelength of 455 nm was irradiated for 24 h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-((2′-fluoro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 55%. The structural formula of the target product is as follows:

[0183]

[0184] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0185] 1 H NMR (600MHz, CDCl3) δ7.34-7.31(m,1H),7.19(dd,J=7.2,0.6Hz,1H),7.10-7.08(m,1H),6.86(d,J=7 .8Hz,1H),6.07-6.03(m,1H),5.67-5.63(m,1H),5.35-5.31(m,1H),3.25(s,3H),3.16-3.01(m,2H).

[0186] 13 C NMR (150MHz, CDCl3) δ175.3, 154.9 (d, J = 250.5Hz), 143.9, 130.6, 129.3, 126.8 (d, J = 1.5Hz), 124.5, 124.3 (d, J = 6.0Hz), 123.2, 108.5, 103.9 (d, J = 16.5Hz), 53.7 (d, J = 27.0Hz), 26.9, 26.5 (d, J = 6.0Hz).

[0187] 19 F NMR (565MHz, CDCl3) δ-116.3.

[0188] HRMS Calcd for C 14 H 13FNO[M+H] + :m / z 230.0976,Found:230.0975.

[0189] Embodiment 25

[0190] 2-((3′-fluoro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2 mmol), LiOH (2.5 equivalents, 0.5 mmol) and catalyst 4CzIPN (5 mol%) were added to a 10 mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3 mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED light with a power of 10 W and a wavelength of 455 nm was irradiated for 24 h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-((3′-fluoro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 49%. The structural formula of the target product is as follows:

[0191]

[0192] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0193] 1 H NMR (600MHz, CDCl3) δ7.32-7.29(m,1H),7.13(d,J=7.2Hz,1H),7.08-7.06(m,1H),6.85(d,J=7.8Hz,1 H), 6.04-6.00 (m, 1H), 5.32 (d, J = 9.6Hz, 1H), 5.00 (d, J = 16.2Hz, 1H), 3.23 (s, 3H), 3.17-3.01 (m, 2H).

[0194] 13 C NMR (150MHz, CDCl3) δ177.3 (d, J = 3.0Hz), 160.7 (d, J = 256.5Hz), 142.9, 133.1, 129.0, 125.2 (d, J = 10.5Hz), 125.0, 124.6 (d, J = 3.0Hz), 123.3, 108.4, 101.4 (d, J = 19.5Hz), 53.6 (d, J = 9.0Hz), 26.9, 26.8 (d, J = 25.5Hz).

[0195] 19 F NMR (565MHz, CDCl3) δ-101.9.

[0196] HRMS Calcd for C 14 H 13 FNO[M+H] + :m / z 230.0976,Found:230.0973.

[0197] Embodiment 26

[0198] 2-((3′-chloro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid (0.2 mmol), LiOH (2.5 equivalents, 0.5 mmol) and catalyst 4CzIPN (5 mol%) were added to a 10 mL reaction tube equipped with a magnetic electron, and NMP / H2O (volume ratio 80:1, 3 mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED light with a power of 10 W and a wavelength of 455 nm was used for 24 h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-((3′-chloro-[1,1′-biphenyl]-2-yl)(methyl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 65%. The structural formula of the target product is as follows:

[0199]

[0200] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0201] 1 H NMR (400MHz, CDCl3) δ7.33-7.29(m,1H),7.13-7.05(m,2H),6.85(d,J=7.6Hz,1 H),6.08-6.03(m,1H),5.52-5.51(m,1H),5.39-5.35(m,1H),3.27-3.07(m,5H).

[0202] 13 C NMR (100MHz, CDCl3) δ176.6,143.0,133.5,132.6,129.1,126.6,125.0,123.5,123.3,121.3,108.4,54.5,33.3,26.8.

[0203] HRMS Calcd for C 14 H 13 ClNO[M+H] + :m / z 246.0680,Found:246.0683.

[0204] Embodiment 27

[0205] 2-(Methyl(3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid (0.2 mmol), LiOH (2.5 equivalents, 0.5 mmol) and catalyst 4CzIPN (5 mol%) were added to a 10 mL reaction tube equipped with a magnetic rod, and NMP / H2O (volume ratio 80:1, 3 mL) was added after vacuuming and backfilling with Ar gas three times. Under an argon atmosphere, a blue LED light with a power of 10 W and a wavelength of 455 nm was irradiated for 24 h, and the reaction was stirred at room temperature. After the reaction was completed, the reaction was quenched with a saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain a yellow oil. Based on the molar amount of 2-(methyl(3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)amino)-2-oxoacetic acid as 100%, the yield of the target product is 67%. The structural formula of the target product is as follows:

[0206]

[0207] The yellow oil was subjected to NMR and mass spectrometry analysis, and the data were as follows:

[0208] 1 H NMR (600MHz, CDCl3) δ7.36-7.32(m,1H),7.10-7.08(m,2H),6.88(d,J=7.8Hz,1H),6.2 1-6.18(m,1H),6.00-5.98(m,1H),5.45-5.42(m,1H),3.25(s,3H),3.13-2.98(m,2H).

[0209] 13 C NMR (100MHz, CDCl3) δ176.1,143.1,132.3,129.4,128.9(q,J=31.0Hz),126.6(q,J= 6.0Hz), 125.8, 125.1, 123.5 (q, J = 271.0Hz), 123.4, 123.3, 108.5, 51.9, 26.9, 23.3.

[0210] 19 F NMR (565 MHz, CDCl3) δ -69.7.

[0211] HRMS Calcd for C 15 H 13 F3NO[M+H] + :m / z 280.0944,Found:280.0944.

[0212] Embodiment 28

[0213] In vitro antitumor activity assay

[0214] method:

[0215] The in vitro anti-Ramos cell proliferation test used the CellTiter-Glo (Promega, USA) test method. After the Ramos cell suspension was diluted to an appropriate concentration using culture medium, 95 μL was added to a 96-well plate. After adding 5 μL of the test compound at different concentrations, the culture plate was incubated at 37°C and 5% CO2 for 72 hours. The culture plate was removed and placed at room temperature to start the test. 20 μL of CellTiter-Glo reagent was added to each well and mixed on a shaker for 2 minutes to induce cell lysis. Incubate at room temperature for 10 minutes to stabilize the fluorescence signal. Use a multifunctional microplate reader to record the fluorescence intensity. Calculate the cell viability based on the formula and the fluorescence intensity of the blank control group, and then calculate the IC of the target compound. 50 .

[0216] The in vitro anti-HeLa or A549 cell proliferation test used Cell Counting Kit-8 (CCK8, DOJINDO, Japan) (Test method. After HeLa or A549 cells were diluted to an appropriate concentration using culture medium, 100 μL was added to a 96-well plate. The cells were incubated overnight at 37°C and 5% CO2. After adding different concentrations of the test compound, the culture plate was incubated at 37°C and 5% CO2 for 72 h. 10 μL of CCK8 reagent was added to each well and incubated at 37°C for 2 h. The absorption intensity at 450 nM and 630 nM was recorded using a multifunctional microplate reader to calculate the IC of the target compound. 50 .

[0217] Table 1 In vitro antitumor activity of representative compounds

[0218]

[0219] The compounds prepared in Examples 13, 17, 25 and 26 all showed strong anti-tumor activity, among which the compounds prepared in Examples 13 and 26 had significantly better anti-human B lymphocytoma (Ramos) and lung cancer (A549) activities than the positive control drug 5-FU.

[0220] The basic principles, main features and advantages of the present invention are shown and described above. Without departing from the spirit and scope of the present invention, the present invention may also be subject to various changes and improvements, which all fall within the scope of the present invention to be protected.

Claims

1. A method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds, characterized in that The specific steps are: adding N-biphenyl oxalic acid compound, base and catalyst in a reaction container in sequence, then vacuuming and backfilling with argon gas for multiple times, adding solvent, stirring and reacting at room temperature under argon atmosphere and visible light irradiation to obtain the target product spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compound, wherein the structural formula of the N-biphenyl oxalic acid compound is shown in formula A, and the structural formula of the spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compound is shown in formula B: Wherein R1 is an alkyl group or a substituted alkyl group, and the substituent of the substituted alkyl group is an alkenyl group, an alkynyl group, a phenyl group, an alkoxy group, a trifluoromethyl group, a halogen group or a drug molecule group; R2 is an alkyl group, an alkoxy group, a trifluoromethyl group or a halogen group; R3 is an alkyl group, an alkoxy group, a trifluoromethyl group or a halogen group; the base is one or more of lithium hydroxide, cesium carbonate, potassium hydroxide, potassium carbonate or sodium carbonate; the catalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, and the structural formula of the catalyst is:

2. The method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds according to claim 1, characterized in that: The alkyl group in R1 is C 1-10 Alkyl, the substituted alkyl in R1 is C 1-10 Substituted alkyl; the alkyl in R2 is C 1-10 Alkyl, the alkoxy group in R2 is C 1-10 Alkoxy; the alkyl group in R3 is C 1-10 Alkyl, the alkoxy group in R3 is C 1-10 Alkoxy.

3. The method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds according to claim 1, characterized in that: The solvent is a mixed solvent of N-methylpyrrolidone and water, wherein the volume ratio of N-methylpyrrolidone to water is 80:

1.

4. The method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds according to claim 1, characterized in that The structural formula of the spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compound is:

5. The method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds according to claim 1, characterized in that: The molar ratio of the N-biphenyl oxalic acid compound, the base and the catalyst is 1:1-3:0.01-0.

1.

6. The method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds according to claim 1, characterized in that The specific synthetic route is:

7. The method for synthesizing spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds according to claim 1, characterized in that: The visible light irradiation condition is to use a blue LED lamp as the visible light source, with a wavelength of 455nm and a power of 10W.

8. Use of the spiro[cyclohexane-1,3'-indoline]-2,5-diene-2'-one compounds prepared according to the method of any one of claims 1 to 7 in the preparation of anti-tumor drugs.

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